RE-ALIGN: Dabigatran in Patients With a Mechanical Heart Valve - - PowerPoint PPT Presentation

RE-ALIGN: Dabigatran in Patients With a Mechanical Heart Valve

Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt

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Background

• Vitamin K antagonists provide effective protection against

thrombosis in patients with a mechanical valve but require food, alcohol and drug restrictions and coagulation monitoring

• Dabigatran 150 mg bid is superior to warfarin in

non-valvular atrial fibrillation (RELY)

• Encouraging preclinical data with dabigatran in porcine

mechanical valve models

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Study design of RE-ALIGN

Start warfarin up to day 7

1 week follow-up or transition to RE-ALIGN extension trial

Warfarin (INR according to guidelines) 12 weeks

Study treatment

CrCl < 70 mL/min: DE 150 mg bid CrCl 70 – < 110 mL/min: DE 220 mg bid CrCl • 110 mL/min: DE 300 mg bid

• Increase dose if dabigatran trough plasma level < 50 ng/mL (by Hemoclot)
• Discontinue dabigatran (switch to nonstudy VKA ) if < 50 ng/mL with 300 mg bid after

2 measurements

Start DE day 3–7 A: Surgery B: Surgery (> 3 months)

Population A Population B

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Population A Population B All patients Dabigatran (n = 133) Warfarin (n = 66) Dabigatran (n = 35) Warfarin (n = 18) Dabigatran (n = 168) Warfarin (n = 84) Death, n (%) 1 (1) 2 (3) 1 (1) 2 (2) Stroke, n (%) 9 (7) 9 (5) SE, n (%) TIA, n (%) 2 (2) 2 (3) 1 (3) 3 (2) 2 (2) MI, n (%) 1 (1) 2 (6) 3 (2) Valve thrombosis without symptoms 2 (2) 3 (9) 5 (3) Death/stroke/SE/ MI, n (%) 11 (8) 2 (3) 2 (6) 13 (8) 2 (2) Death/stroke/TIA/ SE/MI, n (%) 12 (9) 4 (6) 3 (9) 15 (9) 4 (5)

MI, myocardial infarction; SE, systemic embolism; TIA, transient ischaemic attack

Adjudicated efficacy outcomes

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Adjudicated safety outcomes

Population A Population B All patients Dabigatran (n = 133) Warfarin (n = 66) Dabigatran (n = 35) Warfarin (n = 18) Dabigatran (n = 168) Warfarin (n = 84) Major bleeding, n (%) 7 (5) 2 (3) 7 (4) 2 (2) Major bleeding with pericardial location, n (%) 7 (5) 2 (3) 7 (4) 2 (2) Any bleeding, n (%) 35 (26) 8 (12) 10 (29) 2 (11) 45 (27) 10 (12)

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Possible explanations for negative study results

• Inadequate blood levels of dabigatran
• Play of chance with relatively few events seen in the

warfarin arm

• Differences in the mechanism of action of dabigatran

compared with warfarin

• e.g., the inability of dabigatran to suppress activation of

coagulation that occurs when blood is exposed to the artificial surface of prosthetic valves

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Prosthetic valves and contact activation Dabigatran vs. Warfarin

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Xa Thrombin TF/VIIa IXa/VIIIa Clot formation Intrinsic Tenase Extrinsic Tenase X X

Prothrombinase

Warfarin Dabigatran Contact Injury

NEJM, September 1st, 2013

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